Mutation is NOT random

Jonathan Bartlett

Abstract: In evolutionary theory, mutations are thought to be haphazard events, with the primary direction of change being provided by natural selection. Recent discoveries in molecular biology are showing that organisms actually have internal mechanisms which generate mutations in a surprisingly directed manner.

Introduction: Mutations and Evolutionary Theory

Evolution by natural selection is currently the most popular scientific explanation for the origin of biological adaptations. Natural selection is a two-part process. The first part of the process is the generation of new variations, and the second part is the weeding out of less-fit members of the population, so that only the variations which are more fit in the current environment are left.

Notice, however, that in the theory there are two parts, but only one part is named. It is "evolution by natural selection", not "evolution by natural selection of variations". The reason for this is that it is believed that the variations produced in the first part of the process are produced essentially randomly. The specific mechanism for producing variations is purely haphazard, and doesn't need any special attention, because the part of the process which truly shapes the direction of evolution is natural selection. Therefore, it is "evolution by natural selection" because natural selection is the only part of the mechanism providing the direction for the change - everything else is essentially haphazard.

All of this was before the discovery of genes and DNA. DNA is a class of chemicals that provides a storehouse of information within each cell of an organism. It works by taking for different kinds of DNA, known as A, T, C, and G, and strings them together in a sequence which stores the information the cell needs to create and regulate the production of proteins for the cell's functioning. DNA provides information about how to create proteins from their building blocks called amino acids. DNA regulates the production of proteins through a series of promoters and inhibitors which make sure that proteins are produced in the right conditions, and even information on different adjustments which can be made on the proteins being made. Each segment of DNA is called a gene, and the entirety of the information encoded by DNA in a cell is called the genome.

Every generation of organisms receives a copy of the genome, but not exactly the same one as its parents. The genome is organized into sections called chromosomes. Most organisms have two copies of each chromosome - one from each parent. However, the organisms do not inherit exact copies of the chromosomes of its parents. The DNA it receives contains many changes from the parent chromosomes, which it then passes on to its children. These changes are known as mutations.

The modern theory of evolution, then, focuses on changes which occur within the genome, because these changes can be passed on through the generations. Evolution by natural selection, then, focuses on generating variations in the genome, and then keeping the beneficial ones in the population through natural selection. Therefore, in modern evolutionary theory, the sources of new variations for natural selection to act on (to keep or throw away) are the mutations which occur in the genome.

The current theory of natural selection says that the mutations which occur within the genome are random, and are often termed as "copying errors." Therefore, for the evolution of new types of organisms, natural selection is the primary directing force. For proponents of natural selection, the mechanisms by which mutations occur may be interesting, but they are evolutionarily insignificant - it is natural selection which provides the direction, not the mechanisms of mutation. However, recent data from molecular biology is turning this notion on its head. It turns out that mutation is not the haphazard process it was formerly thought to be. In fact, it turns out that organisms have very tightly controlled mechanisms for producing mutations. Thus, as we will see, in many cases the direction of change for a population of organisms may be directed more by the organism's own internal mutational mechanisms than by natural selection. This gives us a dramatically different picture of the character, causes, and possibilities within natural history.

What is meant by random, and why is it important?

There are several different types of randomness, and each of them has slightly different meanings and sometimes drastically different implications. All of them involve some sense of unpredictability, but that is as far as they are similar. We will look at three different kinds of randomness.

Probably the simplest form of randomness is non-correlation. Think of your favorite type of food. Now think of your favorite book. Now, there are a lot of reasons for someone to have a favorite food, and a lot of reasons for someone to have a favorite book, but there is rarely a relationship between the two. Knowing someone's favorite book doesn't tell us anything about what they are likely to have as a favorite food, and vice-versa. This is non-correlation. It simply means that, given two quantities, while they are each likely to have a perfectly good cause on their own, they have no relationship between each other.

Another form of randomness is statistical randomness. Statistical randomness is like a slot machine. Slot machines are designed so that each possible outcome will be achieved at a very steady pace, but the outcome of each individual pull of the lever will not be knowable. So the percentage chances of each possibility are essentially fixed (at least over the long term), but the specific sequence cannot be determined ahead-of-time.

The final form of randomness I will discuss is philosophical randomness. Philosophical randomness is an event which occurs outside the control of a system. When you think about a slot machine, even though the outcomes are statistically random, the system is built so that the owners of the slot machine have a guaranteed amount of money they will earn. Because the chances are fixed, the long-term behavior of the system is very reliable. In fact, for certain processes, statistical randomness can be utilized so that the long-term behavior of a system is actually _more_ reliable than if deterministic (non-random) means were used. So, using our slot machine example, if statistical randomness describes its normal operation, philosophical randomness would describe what happens if an angry customer beat on it with a baseball bat.

In evolutionary theory, all of these come into play at some point or another. The problem is that, often, evidence for one type of randomness will be used as proof for another type randomness. As you can see, non-correlation does not imply statistical randomness, and statistical randomness does not imply philosophical randomness. These are each very different, even though they are often confused.

There are several common claims made by evolutionists about the general nature of mutations:

1)  Mutations are copying errors made by the cell when it replicates DNA

2)  Mutations are not correlated with the fitness of the organism or the population

3)  Mutations are not correlated with the future needs of the organism

4)  Mutations occur with a fairly reliable (though very small) frequency

Claim #1 is one of the more common descriptions of mutation given by biologists. By calling them "copying errors" it is clear that the type of randomness being referred to is philosophical randomness. Claims #2 and #3 are claims of non-correlation. Claim #4 is a claim of statistical randomness.

Now, as mentioned earlier, evolution by natural selection asserts that natural selection is the main director for the path of evolution, and that the mechanisms of variation are essentially haphazard. If the mechanisms of variation were not haphazard, then natural selection would no longer be the director of evolution - it would be the mechanism which produced the variations. Therefore, claims of philosophical randomness are essential to the theory of natural selection. In fact, of the claims above, even though #2 and #3 are technically claims of non-correlation, they are used as claims of philosophical randomness because survivability is the variable they are not correlated with. Claim #4 has almost no bearing on the question of philosophical randomness, because, as we have shown with the example of the slot machine, some systems not only use randomness to achieve their goals, they rely on them.

Therefore, the remainder of the essay will focus on current evidence that contradicts the first three claims of randomness for mutations. Obviously, some mutations are in fact philosophically random. Exposure to radiation, or chemicals, or honest-to-goodness copying errors actually do occur within the genome, and they are genuinely philosophically random events. However, as the evidence from molecular biology is teaching us, the mutations which are interesting for evolution have turned out to be parts of an exquisite mutational machinery, not haphazard changes.

Generating diversity in the immune system

One of the many awe-inspiring systems within the cell is the immune response system. One part of the system are immunoglobulin proteins. Immunoglobulins attach to the outside of B Cells in the immune system, and they are used to attach to foreign invaders within the body. Your body has millions of different immunoglobulins, but they are all coded from a relatively small set of genes. The way this works is that the genome has several different batches of interlocking parts. As the B Cells mature, the cells take one piece from each batch and put them together. In at least some cases, if the pieces don't fit right to make a functioning immunoglobulin, the cell can actually patch them slightly to make them function.

By having an assortment of pieces, the immune system can have millions or even billions of immunoglobulins, just based on choosing different pieces from each batch. This allows the immunoglobulins to attach to a wide variety of differently-shaped invaders. The part of the immunoglobulin that undergoes this batch assembly is called the variable region. At the base of the immunoglobulin is the constant region, which determines the class of immunoglobulin, and attaches to the B cell. It is a very interesting pattern - the part of the protein which interacts with the cells internal systems is very regular and static, which allows the cell to function predictably. However, the part of the protein which interfaces with foreign substances has a huge, dynamic variety.

In any case, this is not the whole story. When the immune system undergoes a challenge, not only does it have millions of immunoglobulins available to make a fit onto the foreign antigen, it then refines the fit of the variable region of the immunoglobulin so that it has a higher affinity towards the antigen. The process which does this is called somatic hyper-mutation, often abbreviated SMH. "Somatic" means that the process is happening in cells other than sperm or egg cells. "hyper-mutation" means that the cell's DNA is undergoing rapid changes. And this is where it gets interesting.

Out of all the genes in the cell, the gene which undergoes hyper-mutation is precisely the gene which needs refinement - namely, the immunoglobulin gene. Within the immunoglobulin gene, nearly all of the mutations take place in the variable region of the gene (which affects antigen binding) and nearly none of them take place in the constant region (which affects overall cell functioning). So the mutations are not only targeted at the correct gene, but they are targeted at the correct locations of the correct gene. These are all controlled by promoters which are in the proper spot for all of this to occur.

Now, the cell does not know _exactly_ which parts of the DNA it needs to modify, nor should we expect it to. However, it is clear that the cell does know which areas of the genome is likely to produce beneficial changes, and mutations are focused on those points. Therefore, it seems that the likelihood of mutations in given regions are in fact correlated with the fitness of the cell. The cell is concentrating its mutations in the areas which are likely to produce benefits. As such, the claim that such mutations are "copying errors" seems to be a nearly laughable category error. Clearly, in the case of the immune system, the direction that the mutations are taking are primarily directed by the cells mutational machinery, and natural selection, while it is operating, is taking a far more subordinate role.

What does evolution in action look like?

Single-celled organisms are interesting creatures to study. Many single-celled organisms, such as E. coli, reproduce quickly, take up a small amount of space, and everything that there is to see happens within one cell. The generation time for bacteria is 20 minutes (compared with 20 years for humans) and you can have trillions of them in a tiny space. Therefore, for watching evolution happen, they are quite ideal. In 57 years, you can have the same number of generations for evolution that you would have if you watched the evolution of humans for three million years.

Because of these properties, many experiments have been done on single-celled organisms to discover the character of evolution. What we are finding over and over again is that the most interesting changes we observe are primarily based on one of two types of evolutionary mechanisms:

* Mechanisms which produce diversity ahead-of-time

* Mechanisms which produce diversity in response to stress